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WO2013038189A1 - Nouveaux composés inhibiteurs d'enzymes - Google Patents

Nouveaux composés inhibiteurs d'enzymes Download PDF

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Publication number
WO2013038189A1
WO2013038189A1 PCT/GB2012/052265 GB2012052265W WO2013038189A1 WO 2013038189 A1 WO2013038189 A1 WO 2013038189A1 GB 2012052265 W GB2012052265 W GB 2012052265W WO 2013038189 A1 WO2013038189 A1 WO 2013038189A1
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alkyl
amino
membered heterocyclyl
mmol
pyridin
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PCT/GB2012/052265
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English (en)
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Allison Carley
Iain Simpson
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Proximagen Ltd.
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Priority to AU2012308153A priority Critical patent/AU2012308153A1/en
Priority to EA201490450A priority patent/EA023803B1/ru
Priority to CN201280044629.5A priority patent/CN103797012A/zh
Priority to EP12761791.8A priority patent/EP2755975A1/fr
Priority to SG11201400278TA priority patent/SG11201400278TA/en
Priority to BR112014005581A priority patent/BR112014005581A2/pt
Priority to US14/344,436 priority patent/US20140275063A1/en
Priority to JP2014530312A priority patent/JP2014526495A/ja
Priority to CA2847266A priority patent/CA2847266A1/fr
Publication of WO2013038189A1 publication Critical patent/WO2013038189A1/fr
Priority to IL231352A priority patent/IL231352A0/en

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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Definitions

  • the present invention relates to compounds which are inhibitors of SSAO activity.
  • the invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment or prevention of medical conditions wherein inhibition of SSAO activity is beneficial, such as inflammatory diseases, immune disorders and the inhibition of tumour growth.
  • SSAO Semicarbazide-sensitive amine oxidase activity is an enzyme activity expressed by Vascular Adhesion Protein-1 (VAP-1 ) or Amine Oxidase, Copper Containing 3 (AOC3), belongs to the copper-containing amine oxidase family of enzymes (EC.1.4.3.6). Therefore inhibitors of the SSAO enzyme may also modulate the biological functions of the VAP-1 protein.
  • VAP-1 Vascular Adhesion Protein-1
  • AOC3 Amine Oxidase, Copper Containing 3
  • TPQ cupric ion and protein-derived topa quinone
  • Known substrates for human SSAO include endogenous methylamine and aminoacetone as well as some xenobiotic amines such as benzylamine [Lyles, Int. J. Biochem. Cell Biol. 1996, 28, 259-274; Klinman, Biochim. Biophys. Acta 2003, 1647(1-2), 131 -137; Matyus et al., Curr. Med. Chem. 2004, 11(10), 1285-1298; O'Sullivan et al., Neurotoxicology 2004, 25(1-2), 303-315].
  • tissue-bound human SSAO is a homodimeric glycoprotein consisting of two 90-100 kDa subunits anchored to the plasma membrane by a single N-terminal membrane spanning domain [Morris et al., J. Biol. Chem. 1997, 272, 9388-9392; Smith et al., J. Exp. Med. 1998, 188, 17-27; Airenne et al., Protein Science 2005, 14, 1964-1974; Jakobsson et al., Acta Crystallogr. D Biol. Crystallogr. 2005, 61 (R 11), 1550-1562].
  • SSAO activity has been found in a variety of tissues including vascular and nonvascular smooth muscle tissue, endothelium, and adipose tissue [Lewinsohn, Braz. J. Med. Biol. Res. 1984, 77, 223-256; Nakos & Gossrau, Folia Histochem. Cytobiol. 1994, 32, 3-10; Yu et al., Biochem. Pharmacol. 1994, 47, 1055-1059; Castillo et al., Neurochem. Int. 1998, 33, 415-423; Lyles & Pino, J. Neural. Transm. Suppl. 1998, 52, 239-250; Jaakkola et al., Am. J. Pathol.
  • SSAO protein is found in blood plasma and this soluble form appears to have similar properties as the tissue-bound form [Yu et al., Biochem. Pharmacol. 1994, 47, 1055-1059; Kurkijarvi et al., J. Immunol. 1998, 767, 1549-1557]. It has recently been shown that circulating human and rodent SSAO originates from the tissue-bound form [Goktijrk et al., Am. J. Pathol.
  • SSAO plays a role in both GLUT4-mediated glucose uptake [Enrique-Tarancon et al., J. Biol. Chem. 1998, 273, 8025-8032; Morin et al., J. Pharmacol. Exp. Then 2001 , 297, 563-572] and adipocyte differentiation [Fontana et al., Biochem. J. 2001 , 356, 769-777; Mercier et al., Biochem. J. 2001 , 358, 335-342].
  • SSAO has been shown to be involved in inflammatory processes where it acts as an adhesion protein for leukocytes [Salmi & Jalkanen, Trends Immunol. 2001 , 22, 21 1 - 216; Salmi & Jalkanen, in 'Adhesion Molecules: Functions and Inhibition" K. Ley (Ed.), 2007, pp. 237-251 ], and might also play a role in connective tissue matrix development and maintenance [Langford et al., Cardiovasc. Toxicol. 2002, 2(2), 141 -150; Goktijrk et al., Am. J. Pathol. 2003, 763(5j, 1921 -1928].
  • SSAO activity in blood plasma is elevated in conditions such as congestive heart failure, diabetes mellitus, Alzheimer's disease, and inflammation [Lewinsohn, Braz. J. Med. Biol. Res. 1984, 17, 223-256; Boomsma et al., Cardiovasc. Res. 1997, 33, 387-391 ; Ekblom, Pharmacol. Res. 1998, 37, 87-92; Kurkijarvi et al., J.
  • SSAO knockout animals are phenotypically overtly normal but exhibit a marked decrease in the inflammatory responses evoked in response to various inflammatory stimuli [Stolen et al., Immunity 2005, 22(1), 105-1 15].
  • antagonism of its function in wild type animals in multiple animal models of human disease e.g.
  • VAP-1 has also been implicated in the progression and maintenance of fibrotic diseases including those of the liver and lung. Weston and Adams (J Neural Transm. 2011 , 1 18(7), 1055-64) have summarised the experimental data implicating VAP-1 in liver fibrosis, and Weston et al (EASL Poster 2010) reported that blockade of VAP-1 accelerated the resolution of carbon tetrachloride induced fibrosis. In addition VAP-1 has been implicated in inflammation of the lung (e.g.
  • VAP-1 blockers would reduce lung inflammation and thus be of benefit to the treatment of cystic fibrosis by treating both the pro-fibrotic and proinflammatory aspects of the disease.
  • SSAO VAP-1
  • SSAO is up regulated in gastric cancer and has been identified in the tumour vasculature of human melanoma, hepatoma and head and neck tumours (Yoong KF, McNab G, Hubscher SG, Adams DH. (1998), J Immunol 160, 3978-88.; Irjala H, Salmi M, Alanen K, Gre ' nman R, Jalkanen S (2001 ), Immunol. 166, 6937- 6943; Forster-Horvath C, Dome B, Paku S, et al. (2004), Melanoma Res. 14, 135- 40.).
  • mice bearing enzymically inactive VAP-1 grow melanomas more slowly, and have reduced tumour blood vessel number and diameter. The reduced growth of these tumours was also reflected in the reduced (by 60-70%) infiltration of myeloid suppressor cells. Encouragingly VAP-1 deficiency had no effect on vessel or lymph formation in normal tissue.
  • SSAO inhibitors Small molecules of different structural classes have previously been disclosed as SSAO inhibitors, for example in WO 02/38153 (tetrahydroimidazo[4,5-c]pyridine derivatives), in WO 03/006003 (2-indanylhydrazine derivatives), in WO 2005/014530 (allylhydrazine and hydroxylamine (aminooxy) compounds) and in WO 2007/120528 (allylamino compounds). Additional SSAO inhibitors are disclosed in PCT/EP2009/06201 1 and PCT/EP2009/062018.
  • the invention described here relates to a new class of SSAO inhibitors with biological, pharmacological, and pharmacokinetic characteristics that make them suitable for use as prophylactic or therapeutic agents in a wide range of human inflammatory diseases and immune disorders.
  • This therapeutic capacity is designed to block SSAO enzyme action, reducing the levels of pro-inflammatory enzyme products (aldehydes, hydrogen peroxide and ammonia) whilst also decreasing the adhesive capacity of immune cells and correspondingly their activation and final extra-vasation.
  • Diseases where such an activity is expected to be therapeutically beneficial include all diseases where immune cells play a prominent role in the initiation, maintenance or resolution of the pathology, such as multiple sclerosis, arthritis and vasculitis.
  • the compounds of formula (I) below are inhibitors of SSAO. They are therefore useful for the treatment or prevention of diseases in which inhibition of SSAO activity is beneficial, such as inflammation, inflammatory diseases, immune or autoimmune disorders, and inhibition of tumour growth.
  • R 1 is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from halogen, cyano, Ci -4 -alkyl, halo-Ci -4 -alkyl, Ci -4 alkoxy-Ci.
  • B is a bond, O, NR 4 , -C(O)- or d -3 -alkylene;
  • Q is saturated or partially unsaturated monocyclic 3-7 membered heterocyclic or C 3- 7-cycloalkyl ring; when R 2 is -B-Q-[R 3 ] n , R 3 is independently selected from: 3-7 membered heterocyclyl-, 3-7 membered heterocyclyl-Ci -4 -alkyl-, (3-7 membered heterocyclyl- Ci- 4 -alkyl)-amino-Ci -4 -alkyl-, amino-Ci -4 -alkoxy-Ci -4 -alkyl-, (amino-Ci -4 -alkyl)-amino- d-4-alkyl-, -Ci -4 -alkyl-NR 6 C(0)OR 5 , -Ci -4 -alkyl-NR 6 C(0)NR 4A R 4B , -C 1-4 -alkyl- C(0)NR 4A R 4B , (3-7 membered heterocyclyl-Ci
  • R 10B is:
  • R 4A and R 4B together with the nitrogen to which they are attached form a 3-7 membered cyclic amino group, optionally substituted by one or more substituents selected from: Ci -4 -alkyl, -NR 4A R 4B ; and wherein unless otherwise specified, 3-7 membered heterocyclyl, or the heterocyclyl part of the 3-7 membered heterocyclyl-Ci -4 -alkyl-, (3-7 membered heterocyclyl-Ci -4 -alkyl)- amino-Ci -4 -alkyl-, or (3-7 membered heterocyclyl-Ci -4 -alkyl)-C(0)- group is optionally substituted with one or more substituents selected from oxo, Ci -4 -alkyl-, -C(0)OR 5 , - C(0)R 5 , -C(0)NR 4A R 4B , -NR 4A R 4B , -Ci -4 -alkyl-C(0)NR 4
  • R 4 and R 6 are each independently selected from hydrogen or Ci -4 -alkyl
  • X is selected from the radicals of formulae (1 -16) wherein the bond marked * is attached to R 1 - and the bond marked ** is attached to -R 2 :
  • ⁇ is selected from hydrogen, hydroxyl, amino, -NHR 6 , -OCH 3 ;
  • Z is selected from hydrogen, fluorine, hydroxyl, Ci -4 -alkoxy, halo-Ci -4 -alkyl, CONH 2 , cyano, S0 2 NH 2 , amino, -NHR 6 ;
  • W is selected from H, Ci -4 -alkyl, halo-Ci -4 -alkyl, PROVIDED THAT when R 2 is -B-Q-[R 3 ] n , and R 3 is 3-7 membered heterocyclyl-, the R 3 heterocyclic ring atom directly bonded to Q is not nitrogen.
  • the present invention makes available a compound of formula (I) or a pharmaceutically acceptable salt, or N-oxide thereof:
  • R 1 is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from halogen, cyano, Ci -4 -alkyl, halo-Ci -4 -alkyl, Ci -4 alkoxy-Ci.
  • B is a bond, O, NR 4 , -C(O)- or d -3 -alkylene;
  • Q is saturated or partially unsaturated monocyclic 3-7 membered heterocyclic or C 3- 7-cycloalkyl ring; when R 2 is -B-Q-[R 3 ] n , R 3 is independently selected from: 3-7 membered heterocyclyl-, 3-7 membered heterocyclyl-Ci -4 -alkyl-, (3-7 membered heterocyclyl- Ci- 4 -alkyl)-amino-Ci -4 -alkyl-, amino-Ci -4 -alkoxy-Ci -4 -alkyl-, (amino-Ci -4 -alkyl)-amino- d-4-alkyl-, -Ci -4 -alkyl-NR 6 C(0)OR 5 , -Ci -4 -alkyl-NR 6 C(0)NR 4A R 4B , -C 1-4 -alkyl- C(0)NR 4A R 4B , (3-7 membered heterocyclyl-Ci
  • R 10B is 3-7 membered heterocyclyl- or 3-7 membered heterocyclyl-Ci -4 -alkyl-, or -Ci -4 -alkyl-NR 6 C(0)R 5 ; or when R 2 is -B-R 3 , R 3 is -NR 6 R 11 B , wherein R 11B is 3-7 membered heterocyclyl-Ci -4 - alkyl-;
  • R 4A , R 4B and R 5 are each independently selected from hydrogen, Ci -4 -alkyl-, 3-7 membered heterocyclyl-Ci -4 -alkyl-, amino-Ci -4 -alkyl-, 3-7 membered heterocyclyl-, - Ci -4 -alkyl-NR 6 C(0)OR 5 , C 3 - 7 -cycloalkyl, or R and R together with the nitrogen to which they are attached form a 3-7 membered cyclic amino group, optionally substituted by one or more substituents selected from: C 1-4 -alkyl, -NR 4A R 4B ; unless otherwise specified, 3-7 membered heterocyclyl, or the heterocyclyl part of the 3-7 membered heterocyclyl-Ci -4 -alkyl-, (3-7 membered heterocyclyl-Ci -4 -alkyl)- amino-Ci -4 -alkyl-, or (3-7 membered heterocyclyl
  • R 4 and R 6 are each independently selected from hydrogen or Ci -4 -alkyl
  • X is selected from the radicals of formulae (1 -16) wherein the bond marked * is attached to R 1 - and the bond marked ** is attached to -R 2 :
  • ⁇ is selected from hydrogen, hydroxyl, amino, -NHR 6 , -OCH 3 ;
  • Z is selected from hydrogen, fluorine, hydroxyl, Ci -4 -alkoxy, halo-Ci -4 -alkyl, CONH 2 , cyano, S0 2 NH 2 , amino, -NHR 6 ;
  • W is selected from H, Ci -4 -alkyl, halo-Ci -4 -alkyl, PROVIDED THAT when R 2 is -B-Q-[R 3 ] n , and R 3 is 3-7 membered heterocyclyl-, the heterocyclic ring atom directly bonded to Q is not nitrogen.
  • “compounds with which the invention is concerned” or “compounds of the invention” or “the present compounds”, and the like, includes reference to salts, hydrates, and solvates of such compounds.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • compounds of the invention may form N-oxides, and the invention includes compounds of the invention in their N-oxide form.
  • Ci -4 -alkyl denotes a straight or branched alkyl group having from 1 to 4 carbon atoms.
  • Ci -4 -alkyl all subgroups thereof are contemplated such as Ci -3 -alkyl, Ci -2 -alkyl, C 2-4 -alkyl, C 2- 3-alkyl and C 3-4 -alkyl.
  • Examples of said Ci -4 -alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and ie f-butyl.
  • C 3 -7-cycloalkyl refers to a monocyclic saturated or partially unsaturated hydrocarbon ring system having from 3 to 7 carbon atoms.
  • Examples of said C 3- 7-cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cydoheptenyl.
  • C 3 -7-cycloalkyl For parts of the range "C 3 -7-cycloalkyl" all subgroups thereof are contemplated such as C 3-7 - cycloalkyl, C 3-6 -cycloalkyl, C 3-5 -cycloalkyl, C 3-4 -cycloalkyl, C 4-7 -cycloalkyl, C 4-6 - cycloalkyl, C 4-5 -cycloalkyl, C 5- 7-cycloalkyl, C 5- 6-cycloalkyl, and C 6- 7-cycloalkyl.
  • Ci -4 -alkoxy refers to a straight or branched Ci -4 -alkyl group which is attached to the remainder of the molecule through an oxygen atom.
  • Ci -4 -alkoxy all subgroups thereof are contemplated such as Ci -3 -alkoxy, Ci -2 - alkoxy, C 2 - 4 -alkoxy, C 2- 3-alkoxy and C 3-4 -alkoxy.
  • Examples of said Ci -4 -alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert- butoxy.
  • hydroxy-Ci -4 -alkyl denotes a straight or branched Ci -4 -alkyl group that has one or more hydrogen atoms thereof replaced with OH.
  • examples of said hydroxy-Ci -4 -alkyl include hydroxy methyl, 2-hydroxyethyl and 2,3-dihydroxypropyl.
  • halo-Ci -4 -alkyl denotes a straight or branched Ci -4 -alkyl group that has one or more hydrogen atoms thereof replaced with halogen.
  • halo- Ci -4 -alkyl include fluoromethyl, trifluoromethyl, trichloromethyl and 2-fluoroethyl.
  • cyano-Ci -4 -alkyl denotes a straight or branched Ci -4 -alkyl group that has one or more hydrogen atoms thereof replaced with cyano.
  • examples of said cyano- Ci -4 -alkyl include cyanomethyl, 2-cyanoethyl and 3-cyanopropyl.
  • amino-Ci -4 -alkyl denotes a straight or branched Ci -4 -alkyl group substituted with an amino group.
  • amino-Ci -4 -alkyl group examples include aminomethyl and 2-aminoethyl.
  • C 1-4 -alkylamino-Ci -4 -alkyl denotes an amino-Ci -4 -alkyl group as defined above, wherein the amino group is substituted with a straight or branched Ci -4 -alkyl group.
  • Examples of said Ci -4 -alkylamino-Ci -4 -alkyl include methylaminoethyl and ethylaminopropyl.
  • di(Ci -4 -alkyl)amino-Ci- 4 -alkyl denotes an amino-Ci -4 -alkyl group as defined above, wherein the amino group is disubstituted with straight or branched Ci -4 -alkyl groups, which can be the same or different.
  • di(Ci -4 - alkyl)amino-Ci -4 -alkyl include ⁇ /,/V-dimethylaminomethyl, /V-ethyl-/V- methylaminoethyl and ⁇ /,/V-diethylaminomethyl.
  • heteroaryl and “heteroaromatic ring” denote a monocyclic heteroaromatic ring comprising 5 to 6 ring atoms in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur or oxygen.
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, tetrazolyl, pyrazolyl, pyridazinyl, pyrazinyl and thiadiazolyl.
  • heterocyclyl and “heterocyclic ring” denote a non-aromatic, fully saturated or partially unsaturated, preferably fully saturated, monocyclic ring system having from 3 to 7 ring atoms, especially 5 or 6 ring atoms, in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur or oxygen.
  • heterocyclic groups include piperidinyl, morpholinyl, homomorpholinyl, azepanyl, piperazinyl, oxo-piperazinyl, diazepinyl, tertahydropyridinyl, tetrahydropyranyl, pyrrolidinyl, tertrahydrofuranyl, and dihydropyrrolyl, groups.
  • heterocyclic-C- -alkyl refers to a heterocyclic ring that is directly linked to a straight or branched Ci -4 -alkyl group via a carbon or nitrogen atom of said ring.
  • heterocyclic-Ci -4 -alkyl include piperidin-4-ylmethyl, piperidin-1 - ylmethyl, morpholin-4-yl-methyl and piperazin-4-ylmethyl.
  • the Ci -4 -alkyl part which includes methylene, ethylene, propylene or butylene, is optionally substituted by one or more substituents selected from halogen, amino, methoxy, or hydroxyl.
  • C 1-3 -alkylene denotes a straight or branched divalent saturated hydrocarbon chain having from 1 to 3 carbon atoms.
  • the Ci -3 -alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain.
  • Examples of Ci -3 - alkylene radicals include methylene [-CH 2 -], 1 ,2-ethylene [-CH 2 -CH 2 -], 1 , 1 -ethylene [-CH(CH 3 )-], 1 ,2-propylene [-CH 2 -CH(CH 3 )-] and 1 ,3-propylene [-CH 2 -CH 2 -CH 2 -].
  • Ci -3 -alkylene all subgroups thereof are contemplated, such as Ci -2 -alkylene and C 2-3 -alkylene.
  • Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine, most preferably fluorine.
  • Haldroxy refers to the -OH radical.
  • “Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • Treatment includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established.
  • An effective amount refers to an amount of a compound that confers a therapeutic effect on the treated subject.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • Prodrugs refers to compounds that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, e.g. by hydrolysis in the blood.
  • the prodrug compound usually offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see Silverman, R. B., The Organic Chemistry of Drug Design and Drug Action, 2 nd Ed., Elsevier Academic Press (2004), pp. 498-549).
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups, such as a hydroxy, amino or mercapto groups, present in a compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Examples of prodrugs include, but are not limited to, acetate, formate and succinate derivatives of hydroxy functional groups or phenyl carbamate derivatives of amino functional groups.
  • a given chemical formula or name shall also encompass all salts, hydrates, solvates, N-oxides and prodrug forms thereof. Further, a given chemical formula or name shall encompass all tautomeric and stereoisomeric forms thereof.
  • Tautomers include enol and keto forms.
  • Stereoisomers include enantiomers and diastereomers.
  • Enantiomers can be present in their pure forms, or as racemic (equal) or unequal mixtures of two enantiomers.
  • Diastereomers can be present in their pure forms, or as mixtures of diastereomers.
  • Diastereomers also include geometrical isomers, which can be present in their pure c/ ' s or trans forms or as mixtures of those.
  • the compounds of formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof.
  • pharmacologically acceptable addition salts mentioned below are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form.
  • Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
  • Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like.
  • organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluen
  • Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
  • the term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.
  • X may be selected from any one of the radicals of formula 1 -16.
  • X is: the formula 1 and R 1 , R 2 , Y, Z and W are as defined above; or the formula 2 and R 1 , R 2 , Y, Z and W are as defined above; or
  • R 1 , R 2 , Y, and Z are as defined above.
  • B is a bond, O, NR 4 such as NH, NCH 3 , or NCH 2 CH 3 , -C(O)- or Ci -3 alkylene such as methylene, ethylene or propylene radicals.
  • B is a bond, -C(O)- or methylene.
  • B is a bond.
  • Y is selected from hydrogen, hydroxyl, amino (NH 2 ), -NHR 6 such as NHCH 3 , NHCH 2 CH 3 , or -OCH 3 .
  • Y is H, OH, or NH 2 .
  • Y is hydrogen
  • Z is selected from hydrogen, fluorine, hydroxyl, Ci -4 -alkoxy such as methoxy or ethoxy, halo-Ci -4 -alkyl such as fluoromethoxy, difluoromethyoxy or trimethoxy, CONH 2 , cyano, S0 2 NH 2 , amino, -NHR 6 such as NHCH 3 , NHCH 2 CH 3 .
  • Z is hydrogen or hydroxyl.
  • W is selected from H, Ci -4 -alkyl such as methyl, ethyl, propyl, isopropyl, or halo-Ci -4 -alkyl such as fluoromethyl, difluoromethyl or trifluoromethyl.
  • W is hydrogen.
  • R 1 is phenyl or 6-membered heteroaryl such as pyridine, pyridazine, pyrimidine, pyrazine, optionally substituted with one or more substituents selected from halogen such as chloro or fluoro, cyano, Ci -4 -alkyl such as methyl, ethyl, propyl or isopropyl, halo-Ci -4 -alkyl such as fluoromethyl, difluoromethyl or trifluoromethyl, Ci -4 alkoxy-Ci -4 alkyl, hydroxy-Ci -4 -alkyl such as hydroxylmethyl or hydroxylethyl, cyano-Ci -4 -alkyl such as cyanomethyl or cyanoethyl, amino-Ci -4 -alkyl such as aminomethyl, aminoethyl or aminopropyl, Ci -4 - alkylamino-Ci -4 -alkyl, di(halogen such as chlor
  • R 1 is optional substituted with one or more substituents selected from halogen such as fluoro or chloro, cyano, hydroxyl, Ci -4 -alkyl such as methyl or ethyl, halo-Ci -4 -alkyl such as fluoromethyl, difluoromethyl or trifluoromethyl, Ci -4 alkoxy-Ci -4 alkyl, hydroxy-Ci -4 -alkyl, cyano-Ci -4 - alkyl such as cyanomethyl or cyanoethyl, amino-Ci -4 -alkyl, Ci -4 -alkylamino-Ci -4 -alkyl, di(Ci -4 -alkyl)amino-Ci -4 -alkyl, -NR 4A R 4B .
  • halogen such as fluoro or chloro
  • cyano, hydroxyl Ci -4 -alkyl such as methyl or ethyl
  • R 1 is heteroaryl such as pyridine-2-yl, pyridine-3-yl or pyridine-4-yl optionally substituted with one or more substituents selected from as fluoro, chloro, and Ci -4 -alkyl such as methyl, ethyl, propyl, or isopropyl.
  • R 1 is phenyl, optionally substituted at one or more of the para-, meta- and ortho- positions by one or more substituents selected from hydrogen, fluoro, chloro, cyano, hydroxyl, Ci -4 -alkyl such as methyl, ethyl, propyl or isopropyl, or fluoromethyl, difluoromethyl, or trifluoromethyl.
  • R 1 is phenyl substituted at the para position by a substituent selected from, fluoro, chloro, cyano, hydroxyl, Ci -4 -alkyl such as methyl, ethyl, propyl or isopropyl, or fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the para substituent is selected from fluoro, chloro or methyl.
  • R 1 is phenyl substituted at the meta- position by hydrogen. In a further currently preferred embodiment R 1 is phenyl substituted at the ortho position by a substituent selected from hydrogen, fluoro, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In another preferred embodiment R 1 is phenyl substituted at the ortho position by hydrogen, fluoro or methyl.
  • R 1 is a mono, di, or tri substituted phenyl ring wherein the ortho, meta and/or para positions may be any combination of the substituents discussed above.
  • the optional substituents of R 1 have a length of 4 atoms or fewer, preferably of 3 atoms or fewer, more preferably of 2 atoms or fewer.
  • R 2 is -B-Q-[R 3 ] n .
  • n can be 1 , 2, 3, or 4. In another currently preferred embodiment n is 1 or 2.
  • the ring Q is a saturated or partially unsaturated monocyclic 3-7 membered heterocyclic or C 3-7 -cycloalkyl ring substituted with R 3 .
  • Q is a 7-membered saturated or partially unsaturated 7-membered heterocyclic ring such as a homomorpholine ring, or a bridged homomorpholine ring wherein the bridge is formed by an ethylene or propylene radical, or a 7-membered cycloalkyi ring such as cycloheptane.
  • Q is a 5- or 6-membered saturated or partially unsaturated 5 or 6 membered heterocyclic such as tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, cyclohexyl, or any of the foregoing rings comprising a bridge formed by an ethylene or propylene radical, or a 5 or 6-membered cycloalkyi ring such cyclopentyl or cyclohexyl.
  • Q is piperidinyl, piperazinyl, or morpholinyl.
  • R 2 is -B-Q-[R 3 ] n , wherein R 3 is selected from: (i) 3-7 membered heterocyclyl- such as 2-, or 4-pyrrolidyl, 2-, 3-, or 4-piperidinyl, 2-, or 3-piperazinyl, or 2- or 3-morpholinyl; 3-7 membered heterocyclyl-C-i -4 -alkyl- such as piperidin-4-ylmethyl, piperidin-1 -ylmethyl, morpholin-4-yl-methyl, morpholin- 2-yl-methyl, and morpholin-3-yl-methyl and piperazin-4-ylmethyl, piperazin-2- ylmethyl or piperazin-3-ylmethyl, or piperidin-4-ylethyl, piperidin-1 -ylethyl, morpholin-4-yl-ethyl, morpholin-2-yl-ethyl, and morpholin-3-yl-ethyl and pipe
  • the cyclic amino group is pyrrolidyl, piperidinyl, piperazinyl, or morpholinyl each of which is substituted on a ring carbon or nitrogen atom by one or more substituents selected from methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, methoxyethyl, cyclopropyl or cyclobutyl.
  • the cyclic amino group is piperazinyl substituted on the 4-position by methyl, ethyl, propyl, iso-propyl, sec-butyl, or cyclopropyl, or
  • R 10B is 3-7 membered heterocyclyl- such as defined above, or 3-7 membered heterocyclyl-Ci -4 -alkyl- such as defined above, or -Ci -4 - alkyl-NR 6 C(0)R 5 ; or
  • R 10B is 5 or 6 membered heteroaryl-Ci -4 -alkyl- such as tetrazolylmethyl, wherein the heteroaryl ring is optionally substituted with one or more substituents selected from Ci-4-alkyl or halo-Ci -4 -alkyl, and wherein the C-M-alkyl part of the heteroaryl-Ci -4 - alkyl- group is optionally substituted by one or more Ci -4 -alkyl- groups, or the Ci -4 - alkyl part is substituted with two Ci -4 -alkyl groups which, together with the carbon atom to which they are attached, join together to form a spiro 3-6 membered cycloalkyl ring.
  • R 10B is tetrazolylmethyl-, wherein the tetrazole group is optionally substituted with one or more substituents selected from Ci-4-alkyl or halo-Ci -4 -alkyl, and wherein the methyl of the tetrazolylmethyl is substituted with two Ci -4 -alkyl groups which, together with the carbon atom to which they are attached, join together to form a spiro cyclopropyl, cyclobutyl or cyclopentyl group.
  • the groups R 4A , R 4B and R 5 are each independently selected from hydrogen, Ci -4 - alkyl- such as methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 3-7 membered heterocyclyl-Ci -4 -alkyl- as defined previously, amino-Ci -4 -alkyl- such as aminomethyl, amino ethyl, 3-7 membered heterocyclyl- as defined above, -Ci -4 - alkyl-NR 6 C(0)OR 5 , or C 3- 7-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopently, cyclohexyl, or R 4A and R 4B together with the nitrogen to which they are attached form a 3-7 membered cyclic amino group such as pyrrolidyl, piperidinyl, homopiperidinyl, piperazinyl, homo
  • the 3-7 membered heterocyclyl (other than the ring Q), or the heterocyclyl part of the 3-7 membered heterocyclyl-Ci -4 -alkyl-, (3- 7 membered heterocyclyl-Ci- 4 -alkyl)-amino-Ci- 4 -alkyl-, or (3-7 membered heterocyclyl-Ci- 4 -alkyl)-C(0)- group is optionally substituted with one or more substituents selected from oxo, Ci -4 -alkyl- such as methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, -C(0)OR 5 , -C(0)R 5 , -C(0)NR 4A R 4B , -NR 4A R 4B such as - NH 2 , -NHCH 3 , NHCH 2 CH 3 , or N(CH 3 )
  • the R 3 group includes a divalent radical -Ci -4 - alkyl- directly attached to the Q ring, such that R 3 may be, for example 3-7 membered heterocyclyl-Ci -4 -alkyl-, (3-7 membered heterocyclyl-Ci -4 -alkyl)-amino-Ci- 4-alkyl-, amino-Ci- 4 -alkoxy-Ci- 4 -alkyl-, (amino-Ci- 4 -alkyl)-amino-Ci- 4 -alkyl-, -Ci -4 -alkyl- NR 6 C(0)OR 5 , -Ci -4 -alkyl-NR 6 C(0)NR 4A R 4B , or -Ci -4 -alkyl-C(0)NR 4A R 4B .
  • -Ci -4 -alkyl- radical is optionally substituted with one or more groups independently selected from halogen, amino, methoxy, and hydroxyl.
  • the -Ci -4 -alkyl- radical is selected from methylene, ethylene, propylene or butylene, any of which is optionally substituted by one or more groups independently selected from halogen, amino, methoxy, and hydroxyl.
  • the R 3 group includes -CH 2 -C(0)NR 4A R 4B , -(CH 2 ) 2 -C(0)NR 4A R 4B , -(CH 2 ) 3 - C(0)NR 4A R 4B or 3-7 membered heterocyclyl-CH 2 -, 3-7 membered heterocyclyl- (CH 2 ) 2 -, or 3-7 membered heterocyclyl-(CH 2 ) 3 -.
  • R 4 and R 6 are each independently selected from hydrogen or Ci -4 -alkyl such as methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl; and
  • R 2 is -B-R 3 and R 3 is -NR 6 R 11 B , wherein R 11 B is 3-7 membered heterocyclyl-Ci -4 -alkyl- as defined previously and R 6 is as defined previously;
  • R 2 is -B-Q-[R 3 ] n
  • R 3 is:
  • R 6 is methyl or hydrogen and R 10B is a 3-7 membered heterocyclyl- such as piperidinyl including piperidine-4-yl and 1 -methylpiperidine-4-yl or R 10B is a 3-7 membered heterocyclyl-Ci -4 -alkyl- including morpholine-4-ylmethyl, morpholine-4-ylethyl, morpholine-4-ylpropyl, piperidine-4-ylmethyl-, piperidine-4- ylethyl-, piperidine-4-ylpropyl-, piperazine-1 -ylmethyl, or piperazine-1 -ylethyl wherein the nitrogen atom in the piperidine 1 -position or the piperazine 4-position is substituted with a substituent selected from hydrogen, methyl, ethyl, isopropyl, methoxyethyk
  • R 3 is -Ci -4 -alkyl-C(0)NR 4A R 4B where R 4A is hydrogen and R 4B is amino ethyl, or R 4A and R 4B together with the nitrogen to which they are attached form a pyrrolidyl or piperidinyl ring optionally substituted by one or more substituents selected from -NH 2 , -NHCH 3 , NHCH 2 CH 3 , or N(CH 3 ) 2 .
  • nt R 2 is:
  • T is a trivalent nitrogen atom or a methyne (i.e.CH);
  • R 6 is hydrogen or Ci -4 -alkyl such as methyl
  • R 10B is 3-7 membered heterocyclyl- group such as morpholine or piperidine, or 3-7 membered heterocyclyl-Ci -4 -alkyl- such as morpholinylmethyl, morpholinylethyl, morpholinylpropyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl, piperazinylmethyl , piperazinylethyl or piperazinylpropyl any of which heterocyclic rings is optionally substituted by one or more substituents selected from Ci -4 -alkyl- and Ci- 4 alkoxy-Ci -4 alkyl.
  • R 2 is:
  • T is a trivalent nitrogen atom or a methyne (i.e.CH);
  • P is a direct bond or a diradical selected from methylene, ethylene, or propylene;
  • R 6 is hydrogen or Ci -4 -alkyl;
  • R 12 is selected from hydrogen, Ci -4 -alkyl such as methyl, ethyl, propyl, butyl, isopropyl, and Ci -4 alkoxy-Ci -4 alkyl such as methoxyethyk
  • R 2 is:
  • T is a trivalent nitrogen atom or a methyne (i.e.CH);
  • P is a diradical selected from methylene, ethylene, or propylene
  • R 6 is hydrogen or Ci -4 -alkyl
  • R 12 is selected from hydrogen, Ci -4 -alkyl such as methyl, ethyl, propyl, butyl, isopropyl, and Ci -4 alkoxy-Ci -4 alkyl such as methoxyethyk
  • R 2 is:
  • R 3 is -Ci -4 -alkyl-C(0)NR 4A R 4B such as -CH 2 -C(0)NR 4A R 4B , -(CH 2 ) 2 -C(0)NR 4A R 4B , or -(CH 2 ) 3 -C(0)NR 4A R 4B wherein R 4A and R 4B are each independently selected from hydrogen, Ci -4 -alkyl- such as methyl, ethyl, propyl, and amino-Ci -4 -alkyl-, or R 4A and R 4B together with the nitrogen to which they are attached form a 3-7 membered cyclic amino group such as pyrrolidine, piperidine, piperazine or morpholine, any of which is optionally substituted by one or more substituents selected from: C 1-4 -alkyl, or -NR 4A R 4B .
  • R 4A and R 4B are each independently selected from hydrogen, Ci -4 -alkyl- such as methyl, e
  • the R 1 group may be any one of the specific R 1 groups of the corresponding position of any of the examples described herein.
  • the R 2 group may be any one of the specific R 2 groups of the corresponding position of any of the examples described herein.
  • the R 3 group may be any one of the specific R 3 groups of the corresponding position of any of the examples described herein.
  • the invention relates to a compound of formula (I) for use in therapy.
  • the compounds as defined above are useful as inhibitors of SSAO activity. As such, they are useful in the treatment or prevention of conditions and diseases in which inhibition of SSAO activity is beneficial. More specifically, they are useful for the treatment or prevention of inflammation, inflammatory diseases, immune or autoimmune disorders, cystic fibrosis, or inhibition of tumour growth.
  • compounds of formula (I) are useful for the treatment or prevention of arthritis (such as rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis and psoriatic arthritis), synovitis, vasculitis, conditions associated with inflammation of the bowel (such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and irritable bowel syndrome), atherosclerosis, multiple sclerosis, Alzheimer's disease, vascular dementia, pulmonary inflammatory diseases (such as asthma, chronic obstructive pulmonary disease and acute respiratory distress syndrome), fibrotic diseases (including idiopathic pulmonary fibrosis, cardiac fibrosis and systemic sclerosis (scleroderma)), inflammatory diseases of the skin (such as contact dermatitis, atopic dermatitis and psoriasis), systemic inflammatory response syndrome, sepsis, inflammatory and/or autoimmune conditions of the liver (such as autoimmune hepatitis, primary biliary
  • vasculitis including, but not limited to, giant cell arteritis, Takayasu's arteritis, Polyarteritis nodosa, Kawasaki disease, Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, Henoch- Schonlein purpura, cryoglobulinemia, cutaneous leukocytoclastic angiitis and primary angiitis of the central nervous system.
  • vasculitis including, but not limited to, giant cell arteritis, Takayasu's arteritis, Polyarteritis nodosa, Kawasaki disease, Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, Henoch- Schonlein purpura, cryoglobulinemia, cutaneous leukocytoclastic angiitis and primary angiitis of the central nervous system.
  • the compounds of the invention are especially useful for the treatment of rheumatoid arthritis, chronic obstructive pulmonary disease or atopic dermatitis.
  • VAP-1 is up regulated in several cancers, including gastric cancer, melanoma, hepatoma and head and neck tumours and that mice bearing enzymatically inactive VAP-1 grow melanomas more slowly, and in view of the link between VAP-1 and angiogenesis, it is also expected that the compounds of the invention are anti-angiogenic and therefore have utility in the treatment of cancers by inhibition of tumour growth.
  • the invention thus includes the compounds of formula (I) above for use in the treatment or prevention of the above-mentioned conditions and diseases.
  • the invention also includes the use of said compounds in the manufacture of a medicament for the treatment or prevention of the above-mentioned conditions and diseases.
  • the invention furthermore includes methods for treatment or prevention of such conditions and diseases, comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound as defined above.
  • Methods delineated herein include those wherein the subject is identified as in need of a particular stated treatment. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • the methods herein include those further comprising monitoring subject response to the treatment administrations.
  • monitoring may include periodic sampling of subject tissue, fluids, specimens, cells, proteins, chemical markers, genetic materials, etc. as markers or indicators of the treatment regimen.
  • the subject is prescreened or identified as in need of such treatment by assessment for a relevant marker or indicator of suitability for such treatment.
  • the invention provides a method of monitoring treatment progress.
  • the method includes the step of determining a level of diagnostic marker (Marker) (e.g., any target or cell type delineated herein modulated by a compound herein) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof delineated herein, in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof.
  • the level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status.
  • a second level of Marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy.
  • a pre-treatment level of Marker in the subject is determined prior to beginning treatment according to this invention; this pre-treatment level of Marker can then be compared to the level of Marker in the subject after the treatment commences, to determine the efficacy of the treatment.
  • a level of Marker or Marker activity in a subject is determined at least once. Comparison of Marker levels, e.g., to another measurement of Marker level obtained previously or subsequently from the same patient, another patient, or a normal subject, may be useful in determining whether therapy according to the invention is having the desired effect, and thereby permitting adjustment of dosage levels as appropriate. Determination of Marker levels may be performed using any suitable sampling/expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first removed from a subject. Examples of suitable samples include blood, urine, tissue, mouth or cheek cells, and hair samples containing roots. Other suitable samples would be known to the person skilled in the art.
  • Determination of protein levels and/or mRNA levels (e.g., Marker levels) in the sample can be performed using any suitable technique known in the art, including, but not limited to, enzyme immunoassay, ELISA, radiolabeling/assay techniques, blotting/chemiluminescence methods, real-time PCR, and the like.
  • a currently preferred embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), together with one or more pharmaceutically acceptable carriers and/or excipients.
  • the compounds of the invention are formulated into pharmaceutical formulations for various modes of administration. It will be appreciated that compounds of the invention may be administered together with a physiologically acceptable carrier, excipient, or diluent.
  • the pharmaceutical compositions of the invention may be administered by any suitable route, preferably by oral, rectal, nasal, topical (including buccal and sublingual), sublingual, transdermal, intrathecal, transmucosal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • compositions may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy.
  • Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutically acceptable carriers, diluents or excipients.
  • excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
  • Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
  • the amount of active compounds is between 0.1 -95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and more preferably between 1 -50% by weight in preparations for oral administration.
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner. To maintain therapeutically effective plasma concentrations for extended periods of time, compounds of the invention may be incorporated into slow release formulations.
  • the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • the compounds of formula (I) above may be prepared by, or in analogy with, conventional methods.
  • the preparation of intermediates and compounds according to the Examples of the present invention may in particular be illuminated by the following Schemes. Definitions of variables in the structures in Schemes herein are commensurate with those of corresponding positions in the formulas delineated herein.
  • Y, Z, R 1 and R 2 are as defined in formula (I);
  • Compounds of general formula (Ic) can easily be prepared by reductive amination of 3-amino-pyridine-4-carbaldehydes of general formula (lie) to give compounds of general formula (lllc) and subsequent cyclisation to give pyrazolo[3,4-c]pyridines of general formula (IVc).
  • pyrazolo[3,4-c]pyridines of general formula (IVc) can be prepared by cyclisation of (3-fluoropyridin-4-yl)carbonyl compounds of general formula (Vc) with hydrazine.
  • Compounds of general formula (lc) can be prepared from compounds of general formula (IVc) by standard N-arylation reactions.
  • Compounds of general formula (li) can be prepared from 1 H-pyrrolo[2,3- d]pyridazines (IN) by bromination with CuBr (for example, as described in Gallou et al., Syn. Lett., 2, 21 1 -214, 2007) followed by either introduction of R 2 (for example by nucleophilic substitution) followed by R 1 (for example by a Suzuki reaction), or by reversing these steps (with an appropriate protecting group strategy).
  • Compounds of general formula (Ij) can be prepared from 1 H-pyrrolo[2,3- d]pyridazines (llj) by bromination with CuBr (for example, as described in Gallou et al., Syn. Lett., 2, 21 1 -214, 2007) followed by either introduction of R 2 (for example by nucleophilic substitution) followed by R 1 (for example by a Suzuki reaction), or by reversing these steps (with an appropriate protecting group strategy).
  • Compounds of general formula (Ik) can be prepared by cyclisation of compounds of general formula (Ilk) with hydrazines, for example, as described in Deeb et al., Journal of the Chinese Chemical Society, 37(3), 287-94; 1990.
  • Compounds of general formula (II) can be prepared by cyclisation of compounds of general formula (III) with hydrazines, for example, as described in Haider et al., Journal of the Chemical Society, Perkin Transactions 1 : Organic and Bio-Organic Chemistry, 1 , 169-72; 1986.
  • Compounds of general formula (In) can be prepared by cyclisation of compounds of general formula (lln) with hydrazines, for example, as described in Filaok et al., Journal of Organic Chemistry, 73(10), 3900-3906, 2008.
  • a compound of formula (I) can also be transformed into another compound of formula (I) in one or more synthetic steps.
  • Reactions were conducted at room temperature unless otherwise specified. Microwave reactions were performed with a Biotage microwave reactor using process vials fitted with aluminum caps and septa. Hydrogenations were performed using a Thales H-Cube. Preparative flash chromatography was performed on Merck silica gel 60 (230-400 mesh) or using a Flash Master Personal system equipped with Strata SI-1 silica gigatubes, or using a CombiFlash Companion system equipped with RediSep silica columns. Reverse phase column chromatography was performed on a Gilson system (Gilson 321 pump and Gilson FC204 fraction collector) equipped with Merck LiChroprep ® RP-18 (40-63um) columns.
  • Reverse Phase HPLC was performed on a Gilson system with a UV detector equipped with Phenomenex Synergi Hydro RP 150 x 10 mm, or YMC ODS-A 100/150 x 20 mm columns. The purest fractions were collected, concentrated and dried under vacuum. Compounds were typically dried in a vacuum oven at 40 °C prior to purity analysis.
  • Spectra were acquired in positive electrospray mode. The acquired mass range was m/z 100-2000. Samples were dissolved in DMSO to give 10 mM solutions which were then further diluted with MeOH or 10 mM NH 4 OAc in MeOH to -0.1 M solutions prior to analysis). The values reported correspond to the protonated molecular ions [MH] + .
  • the compounds prepared were named using ACD Name 6.0, 7.0 or 10.0.
  • 6-Azaindole (4.48 g, 37.9 mmol) was dissolved in MeOH (70 mL) and KOH (4.68 g, 83.4 mmol) and tert-butyl 4-oxopiperidine-1 -carboxylate (8.31 g, 41.7 mmol) were added.
  • the reaction mixture was heated at 70 °C for 18 h.
  • the residue was partitioned between water (250 mL) and DCM (250 mL) and the aq phase was extracted with DCM (2 x 250 mL).
  • the combined organic fractions were dried (MgSC>4) and concentrated in vacuo to give the title compound as a yellow foam
  • CDI (936 mg, 5.77 mmol) was dissolved in DCM (50 mL), a solution of tert-butyl 4- (aminomethyl)piperidine-l -carboxylate (1 .24 g, 5.77 mmol) and DIPEA (1 .25 mL, 7.22 mmol) in DCM (10 mL) was added and the reaction mixture was stirred for 18 h.
  • Example 40 (50.0 mg, 0.13 mmol) was dissolved in DCM (1 mL), cooled to 0 °C and DIBALH (0.78 mL, 1 .0 M in heptane, 0.78 mmol) was added portion-wise over 6 days. The reaction mixture was stirred for 1 week, cooled to 0 °C and quenched with water (1 mL). The reaction mixture was filtered and concentrated in vacuo to give the crude title compound as a yellow gum (51.0 mg). LCMS (ES + ): 359.0 [MH] + . INTERMEDIATE 49
  • Example 2 (72.0 mg, 19%) was prepared similarly to Example 1 , using tert-butyl 4- oxopiperidine-1 -carboxylate instead of tert-butyl 3-oxopyrrolidine-1 -carboxylate.
  • HRMS calcd for C23H27CIN4 395.1997, found 395.1998.
  • HPLC Rt 3.52 min, 99% purity.
  • Example 3 (39.0 mg, 20%) was prepared similarly to Example 1 , using tert-butyl 4- formylpiperidine-1 -carboxylate instead of tert-butyl 3-oxopyrrolidine-1 -carboxylate.
  • HRMS (ESI+) calcd for C24H29CIN4 409.2153, found 409.2155.
  • HPLC Rt 3.55 min, 99% purity.
  • CDI (187 mg, 1 .15 mmol) was dissolved in DCM (10 ml_), a solution of tert-butyl 4- (aminomethyl)piperidine-l -carboxylate (247 mg, 1 .15 mmol) and DIPEA (251 ⁇ _, 1 .15 mmol) in DCM (2 mL) was added and the reaction mixture was stirred for 18 h.
  • Examples 7-26 were prepared similarly to Example 6, by CDI (or triphosgene) coupling of Intermediate 4 with the appropriate amine, and subsequent Boc deprotection (where required); see Table 4 below.
  • Example 35 (1 .23 mg, 2%) was prepared similarly to Example 34, using Intermediate 19 instead of Intermediate 18 and 1 -methylpiperazine instead of morpholine.
  • Triphosgene (14.2 mg, 0.05 mmol) was dissolved in DCM (1 mL) and a solution of tert-butyl N-(3-hydroxypropyl)carbamate (25.2 mg, 0.14 mmol) and DIPEA (25.0 ⁇ , 0.14 mmol) in DCM (1 mL) was added.
  • the reaction mixture was stirred for 1 h, a solution of Example 36 (50.0 mg, 0.10 mmol) and DIPEA (25.0 ⁇ _, 0.14 mmol) in DCM (1 mL) was added and the reaction mixture was stirred for 4 d.
  • the reaction mixture was diluted with DCM (10 mL) and washed with sat aq NH4CI (5 x 10 mL).
  • Example 38 (24.6 mg, 41 %) was prepared similarly to Example 37, using tert-butyl N-(3-aminopropyl)carbamate instead of tert-butyl N-(3-hydroxypropyl)carbamate.
  • HRMS (ESI+) calcd for C25H33CIN802 513.2488, found 513.2486.
  • Example 41 was prepared similarly to Example 40, by N-arylation of Intermediate 38 to give the title compound as a yellow gum (6.00 mg, 5%).
  • HRMS (ESI+) calcd for C21 H24CIN502 414.1691 , found 414.1693.
  • Example 44 was prepared similarly to Example 40, by N-arylation of Intermediate 35 and subsequent Boc deprotection (HCI in EtOH) to give the title compound as a pale brown gum (2.27 mg, 1 %).
  • HRMS (ESI+) calcd for C18H20CIN5O 358.1429, found 358.1434. HPLC: Rt 4.00 min, 97% purity.
  • EXAMPLE 45
  • Example 45 was prepared similarly to Example 40, by N-arylation of Intermediate 36 and subsequent Boc deprotection (HCI in Et 2 0) to give the title compound as a pale green gum (9.98 mg, 10%).
  • HRMS (ESI+) calcd for C18H21 CIN6 357.1589, found 357.1592. HPLC: Rt 3.57 min, 99.5% purity.
  • Example 45 (24.6 mg, 0.07 mmol) was dissolved in MeOH (2 mL), formaldehyde (55.9 mg, 37 % in water, 0.69 mmol) was added and the reaction mixture was stirred for 30 min. NaBH(OAc) 3 (17.5 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound as a pale green gum (16.0 mg, 63%). HRMS (ESI+) calcd for C19H23CIN6 371.1745, found 371 .1751 . HPLC: Rt 3.54 min, 100% purity.
  • Examples 49-50 were prepared similarly to Example 48, by borane reduction of Intermediate 46 and Boc protected Example 47, and subsequent Boc deprotection; see Table 5 below. Table 5: Borane reduction and subsequent Boc deprotection
  • V NR 9a R 9b or NR 6 R 0b
  • Example 40 (1 .00 g, 2.84 mmol) was dissolved in 1 :1 THF/water (16 mL), LiOH.H 2 0 (262 mg, 6.24 mmol) was added and the reaction mixture was stirred for 3 h. The THF was removed in vacuo and the reaction mixture was acidified to pH 1 with 1 M aq HCI (5 mL). The precipitate was collected by filtration and washed with water to give the title compound as an orange solid (28.3 mg, 3%). HRMS (ESI+) calcd for C18H17CIN403 373.1062, found 373.1062. HPLC: Rt 4.40 min, 97% purity.
  • Example 53 (180 mg, 0.44 mmol) was dissolved in DMF (2.1 mL) and cooled to 0 °C, and HBTU (167 mg, 0.44 mmol), ie/f-butyl N-(2-aminoethyl)carbamate (84.6 mg, 0.53 mmol) and DIPEA (76.6 ⁇ , 0.44 mmol) were added. The reaction mixture was stirred at 0 °C for 2.5 h and purified by column chromatography. The residue was dissolved in 1 .25 M HCI in EtOH (2.5 mL) and stirred for 2 h. The reaction mixture was concentrated in vacuo to give the title compound as an orange solid (46.4 mg, 22%).
  • HRMS (ESI+) calcd for C20H23CIN6O2 415.1644, found 415.1638. HPLC: Rt 3.97 min, 99% purity.
  • Examples 55-58 were prepared similarly to Example 54, by amide coupling to Example 53 (no HCI salt formation step); see Table 6 below. Table 6: Amide couplings to Example 53
  • Example 62 (252 mg, 53%) was prepared similarly to Example 61 , using cyclopropyl(1 H-1 ,2,3,4-tetrazol-5-yl)methanamine instead of 1 H-1 ,2,3,4-tetrazol-5- ylmethanamine hydrochloride.
  • Example 63 (92.0 mg, 19%) was prepared similarly to Example 61 , using 1 -(1 H- 1 ,2,3, 4-tetrazol-5-yl)cyclobutan-1 -amine instead of 1 H-1 ,2,3,4-tetrazol-5- ylmethanamine hydrochloride.
  • Dose-response measurements were assayed by either creating 1 :10 serial dilutions in DMSO to produce a 7 point curve or by making 1 :3 serial dilutions in DMSO to produce 1 1 point curves.
  • the top concentrations were adjusted depending on the potency of the compounds and subsequent dilution in reaction buffer yielded a final DMSO concentration ⁇ 2%.
  • Hydrogen peroxide detection In a horseradish peroxidase (HRP) coupled reaction, hydrogen peroxide oxidation of 10-acetyl-3,7-dihydroxyphenoxazine produced resorufin, which is a highly fluorescent compound (Zhout and Panchuk-Voloshina. Analytical Biochemistry 253 (1997) 169-174; Amplex ® Red Hydrogen Peroxide/peroxidase Assay kit, Invitrogen A22188). Enzyme and compounds in 50 mM sodium phosphate, pH 7.4 were set to pre-incubate in flat-bottomed microtiter plates for approximately 15 minutes before initiating the reaction by addition of a mixture of HRP, benzylamine and Amplex reagent.
  • HRP horseradish peroxidase
  • Benzylamine concentration was fixed at a concentration corresponding to the Michaelis constant, determined using standard procedures. Fluorescence intensity was then measured at several time points during 1 - 2 hours, exciting at 544 nm and reading the emission at 590 nm.
  • final concentrations of the reagents in the assay wells were: SSAO enzyme 1 ⁇ g ml, benzylamine 100 ⁇ , Amplex reagent 20 ⁇ , HRP 0.1 U/mL and varying concentrations of test compound. The inhibition was measured as % decrease of the signal compared to a control without inhibitor (only diluted DMSO). The background signal from a sample containing no SSAO enzyme was subtracted from all data points. Data was fitted to a four parameter logistic model and IC 50 values were calculated using the GraphPad Prism 4 or XLfit 4 programs.
  • SSAO activity was assayed using 14C-labeled benzylamine and analysed by measuring radioactive benzaldehyde.
  • 20 ⁇ _ of diluted test compound was pre-incubated at RT. with 20 ⁇ _ SSAO enzyme for approximately 15 minutes with continuous agitation. All dilutions were made with PBS.
  • the reaction was initiated by adding 20 ⁇ _ of the benzylamine substrate solution containing [7-14C] Benzylamine hydrochloride (CFA589, GE Healthcare). The plate was incubated for 1 hour as above after which the reaction was stopped by acidification (10 ⁇ _ 1 M HCI).

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Abstract

La présente invention concerne des composés de formule (I) qui sont des inhibiteurs de l'amine oxydase R1-X-R2 (I) sensible aux semicarbazides, R1, X et R2 étant tels que définis dans les revendications.
PCT/GB2012/052265 2011-09-14 2012-09-13 Nouveaux composés inhibiteurs d'enzymes WO2013038189A1 (fr)

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AU2012308153A AU2012308153A1 (en) 2011-09-14 2012-09-13 New enzyme inhibitor compounds
EA201490450A EA023803B1 (ru) 2011-09-14 2012-09-13 Ингибиторы ферментов
CN201280044629.5A CN103797012A (zh) 2011-09-14 2012-09-13 新的酶抑制剂化合物
EP12761791.8A EP2755975A1 (fr) 2011-09-14 2012-09-13 Nouveaux composés inhibiteurs d'enzymes
SG11201400278TA SG11201400278TA (en) 2011-09-14 2012-09-13 New enzyme inhibitor compounds
BR112014005581A BR112014005581A2 (pt) 2011-09-14 2012-09-13 compostos inibidores de enzima
US14/344,436 US20140275063A1 (en) 2011-09-14 2012-09-13 New enzyme inhibitor compounds
JP2014530312A JP2014526495A (ja) 2011-09-14 2012-09-13 新規な酵素阻害化合物
CA2847266A CA2847266A1 (fr) 2011-09-14 2012-09-13 Nouveaux composes inhibiteurs d'enzymes
IL231352A IL231352A0 (en) 2011-09-14 2014-03-06 New enzyme inhibitory compounds

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US9150574B2 (en) 2011-09-14 2015-10-06 Proximagen Limited Enzyme inhibitor compounds
US9428498B2 (en) 2013-03-13 2016-08-30 Proximagen Limited Substituted imidazo[4,5-c]pyridine compounds and compositions thereof
US9580415B2 (en) 2013-03-13 2017-02-28 Proximagen Limited Compounds
JP2017520530A (ja) * 2014-05-19 2017-07-27 メリアル インコーポレイテッド 駆虫性化合物
US10065954B2 (en) 2014-09-17 2018-09-04 Proximagen Limited Substituted imidazo[4,5-c]pyridines as SSAO inhibitors
US10508113B2 (en) 2018-03-12 2019-12-17 Abbvie Inc. Inhibitors of tyrosine kinase 2 mediated signaling
EP3777846A1 (fr) 2015-12-07 2021-02-17 BenevolentAI Cambridge Limited Inhibiteurs de vap-1 for traitmanet de la douleur
US11530208B2 (en) 2014-09-17 2022-12-20 Proximagen, Llc Imidazo[4,5-C]pyridine derived SSAO inhibitors

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CA3176881A1 (fr) * 2020-03-25 2021-09-30 Terns, Inc. Traitement de troubles respiratoires
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GB201115853D0 (en) 2011-10-26
JP2014526495A (ja) 2014-10-06
SG11201400278TA (en) 2014-05-29
AU2012308153A1 (en) 2014-03-20
EA023803B1 (ru) 2016-07-29
BR112014005581A2 (pt) 2017-03-21
US20140275063A1 (en) 2014-09-18
CA2847266A1 (fr) 2013-03-21
EP2755975A1 (fr) 2014-07-23
EA201490450A1 (ru) 2014-08-29
IL231352A0 (en) 2014-04-30

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